Atherothrombosis is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Although some of the causes responsible for this finding have been determined (e.g. hypertension, smoking, dyslipidemia) many of other putative mechanisms remain ill-defined. Remarkably, limited specific information exists identifying which of the parameters present in the disordered metabolic milieu occurring in T2DM are mechanisms responsible for the increased prothrombotic state and reduced endothelial function characteristic of this condition. The studies outlined in this proposal are focused on determining the in-vivo "metabolic" mechanisms causing the increased prothrombotic state that occurs in T2DM. Studies will determine whether it is insulin, hyperglycemia or insulin resistance that is a mechanism for disordered fibrinolytic balance and decreased endothelial function in T2DM. Additionally, studies aimed at determining the effects of high glucose, high FFA and basal insulin on fibrinolytic balance will also be proposed. We will introduce a new, clinically relevant area of research by determining the effects of hypoglycemia on endothelial function and vascular fibrinolytic balance in T2DM. Experiments will use the glucose clamp and pituitary-pancreatic-glucose clamp techniques, to precisely control glycemic and endocrine environments during our studies. Endothelial and non-endothelial dependent function will be determined by graded intra-arterial infusions of bradykinin and sodium nitroprusside. Vascular fibrinolytic balance will be determined by measuring plasma PAI-1 and arterial t-PA release. The specific aims of this proposal are to determine: 1) To determine the effects of hyperglycemia per se and hyperinsulinemia per se on disordered fibrinolytic balance and endothelial dysfunction in patients with diabetes, 2) To determine the effects of elevated free fatty acids and hyperglycemia on endothelial function and fibrinolytic balance in patients with type 2 diabetes, 3) To determine the effects of hypoglycemia on fibrinolytic balance in patients with diabetes, and 4) To determine the roles played by corticosteroid receptors on hypoglycemia effects on vascular fibrinolytic balance and endothelial function in patients with type 2 diabetes.